J Gastroenterol 2004; 39:21–25 DOI 10.1007/s00535-003-1240-6

The comparative effects of single intravenous doses of omeprazole and famotidine on intragastric pH Yasunobu Abe, Masahiko Inamori, Jun-Ichi Togawa, Taisuke Kikuchi, Kenichi Muramatsu, Gaku Chiguchi, Harunobu Kawamura, Noritoshi Kobayashi, Hiroyuki Kirikoshi, Takashi Sakaguchi, Tomoo Takamura, Atsushi Nakajima, Norio Ueno, and Hisahiko Sekihara The Third Department of Internal Medicine, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan

Editorial on page 92 Background. The ideal medication for the treatment of acid-related diseases, for example, hemorrhagic ulcers and stress-related gastric bleeding, should have a rapid onset of action to promote hemostasis and alleviate symptoms. The aim of our study was to investigate the inhibitory effects on gastric acid secretion after single intravenous administrations of omeprazole 20 mg and famotidine 20 mg. Methods. Ten healthy Helicobacter pylori-negative male subjects participated in this randomized, double-masked, two-way crossover study. Intragastric pH was monitored continuously for 4 h after a single intravenous administration of omeprazole 20 mg and after a single intravenous administration of famotidine 20 mg. The administration of the two agents was separated by a 7-day washout period. Results. In all ten subjects, the length of time that intragastric pH remained over 3, during the 0- to 3- and 0- to 4-h study periods, was greater after famotidine treatment than after treatment with omeprazole, and famotidine increased the average pH during the 0 to 3- and 0 to 4-h study periods significantly more than omeprazole did. During the 4-h study period, famotidine provided a longer duration of pH of more than 2, 3, 3.5, 4, 5, 6, and 7, compared to omeprazole. Conclusions. In Helicobacter pylori-negative healthy male subjects, an intravenous dose of 20 mg famotidine increased intragastric pH more rapidly than intravenous omeprazole 20 mg. Key words: intragastric acidity, omeprazole, famotidine, proton pump inhibitor, H2 receptor antagonist

Introduction The ideal medication for the treatment of acid-related diseases; for example, hemorrhagic gastric ulcer and stress-related gastric bleeding, should have a rapid onset of action for decreasing intragastric acidity, because in vitro studies have shown that blood coagulation and platelet aggregation are abolished at pH values of less than 5.4.1 Multiple agents, including antacids, H2 receptor antagonists, and proton pump inhibitors, are currently available for treating acid-related conditions. Proton pump inhibitors are the most potent inhibitors of gastric acid secretion when used regularly.2 However, few studies have described the effects of treatment with a single intravenous dose of a proton pump inhibitor or an H2 receptor antagonist, which may be critical in Intensive Care Unit (ICU) and presurgical patients. We designed this study to compare the acute effect of famotidine with that of omeprazole, each given as a single 20-mg intravenous dose, on intragastric pH.

Subjects and methods Subjects This was a double-blind, randomized, two-way crossover study of ten healthy male volunteers (mean age, 28.5 years; range, 22–34 years), who were not users of acid suppressive medications, including antacids, H2 receptor antagonists, and/or proton pump inhibitors. All subjects were negative for anti-Helicobacter pylori immunoglobulin G antibodies (SRL, Tokyo, Japan). Study protocol and pH-metry

Received: January 30, 2003 / Accepted: May 16, 2003 Reprint requests to: M. Inamori

All subjects received intravenously administered omeprazole (Omepral; AstraZeneca, Osaka, Japan), 20 mg, dissolved in 20 ml of saline, and 20 mg famotidine

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(Gaster, Yamanouchi, Tokyo, Japan), dissolved in 20 ml of saline, in random sequence. The drugs were administered separately, with a washout period of at least 7 days between each study. The subjects fasted overnight (for at least 8 h) before treatment and for 4 h after receiving the drug; both drugs were given in the morning. A pH electrode was inserted transnasally, under local anesthesia, and placed in the body of the stomach. The gastric pH was measured at 10-s intervals by a portable pH meter attached to the antimony pH electrode (Chemical Instrument, Tokyo, Japan). The pH electrode was calibrated before each recording, using standard buffers of pH 1.68, 4.01, and 6.86. The pH data were analyzed using established software (Chemical Instrument). The length of time during which intragastric pH remained above 1, 2, 3, 3.5, 4, 5, 6, 7, and 8 during the 4-h monitoring period after each study drug administration was also measured.

Y. Abe et al.: Initial effects of omeprazole and famotidine

Fig. 1. Famotidine 20 mg provided a longer duration of gastric pH at more than 3 during the 0- to 3- and 0- to 4-h study periods, compared to omeprazole 20 mg. Circles and squares, mean values; vertical lines, mean errors. *P ⬍ 0.05; **P ⬍ 0.01

Holding time (%) during which pH remained above 3 CYP2C19 genotyping DNA samples were obtained from white blood cells separated from whole blood samples obtained from the ten subjects. Their S-mephenytoin 4⬘-hydroxylase (CYP2C19) genotype was determined by a polymerase chain reaction-restriction fragment length polymorphism method.3 There are two point mutations of CYP2C19: the wild-type allele has G at position 636 in exon 4 and G at position 689 in exon 5; one of the mutated alleles (the m1 allele) has A at position 689 in exon 5 and the other mutated allele (the m2 allele) has A at position 636 in exon 4.4,5 The CYP2C19 genotyping was done by SRL. Statistics Statistical evaluation was carried out using the Wilcoxon signed-ranks test. The level of significance was P ⬍ 0.05. Statistical analyses were performed using the Stat View program (SAS Institute, Cary, NC, USA). Ethics The study was conducted in accordance with the Helsinki Declaration, and the Ethics Committee of Yokohama City University School of Medicine approved this study.

Results All subjects completed the study. No adverse events were recorded during the study.

Famotidine 20 mg maintained a gastric pH of more than 3 for significantly longer than omeprazole 20 mg during both the 0- to 3-h (mean, 35.9% versus 13.4%; P ⬍ 0.05) and the 0- to 4-h study periods (mean, 38.5% versus 12.0%; P ⬍ 0.01) (Fig. 1). No significant differences were found at the 0- to 1- and 0- to 2-h study periods between the two drugs. Average pH Average pH was significantly higher after the administration of famotidine 20 mg, compared to that after omeprazole 20 mg both during the 0- to 3-h (mean, 5.08 versus 3.08; P ⬍ 0.05) and the 0- to 4-h study periods (mean, 5.36 versus 2.85; P ⬍ 0.01) (Fig. 2). No significant differences were found at the 0- to 1- and 0to 2-h study periods. Holding time (%) at various pH levels during 4-h study period During the 4-h study period, famotidine 20 mg provided a longer duration of pH more than 2, 3, 3.5, 4, 5, 6, and 7, compared to omeprazole 20 mg (mean, 84.9% versus 45.7%; P ⬍ 0.01; 76.2% versus 30.8%; P ⬍ 0.01; 74.5% versus 28.1%; P ⬍ 0.01; 72.4% versus 25.6%; P ⬍ 0.01; 64.0% versus 19.4%; P ⬍ 0.01; 56.9% versus 15.4%; P ⬍ 0.01; and 39.7% versus 8.2%; P ⬍ 0.01, respectively) (Fig. 3). CYP2C19 genotype Six subjects were genotyped as extensive metabolizers, including five homozygous extensive metabolizers with

Y. Abe et al.: Initial effects of omeprazole and famotidine

Fig. 2. Famotidine 20 mg provided higher average pH, compared to omeprazole 20 mg, during the 0- to 3- and 0- to 4-h study periods after administration. Circles and squares, mean values; vertical lines, mean errors. *P ⬍ 0.05; **P ⬍ 0.01

Fig. 3. During the 4-h study period, famotidine 20 mg provided a longer duration of pH more than 2, 3, 3.5, 4, 5, 6, and 7, compared to omeprazole 20 mg. Circles and squares, mean values, vertical lines, mean errors. **P ⬍ 0.01

two wild-type alleles and one heterozygous extensive metabolizer with one wild-type allele and one mutated allele. The other four subjects were genotyped as poor metabolizers with two mutated alleles.

Discussion In this study, we examined the changes in intragastric pH after a single intravenous administration of each of famotidine 20 mg and omeprazole 20 mg in the early post-administration phase in healthy H. pylori-negative subjects. We observed that famotidine had a significantly faster onset of action and stronger inhibition of intragastric acid secretion than omeprazole. These

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study results support the previous reports by Khoury et al.,6 Arnestad et al.,7 Hedenstrom et al.,8 Hurlimann et al.,9 and Chassany et al.10 that H2 receptor antagonists increase intragastric pH more rapidly than proton pump inhibitors. Omeprazole is inactivated by metabolism in the liver, especially by CYP2C19 and CYP3A4 of cytochrome P450. Significant differences in plasma drug levels have been shown between CYP2C19 extensive metabolizers and poor metabolizers, and these differences influence the degree of inhibition of acid secretion.11–15 Famotidine is not metabolized by cytochrome P450;16 therefore, the inhibition of acid secretion by famotidine should be less influenced by the CYP2C19 phenotype or genotype status. The frequency of the poor metabolizer phenotype of CYP2C19 shows considerable interethnic variations: only 2% to 6% of Caucasians are poor metabolizers, as compared with 19% to 23% of Japanese.3,17,18 Four of the ten subjects (40%) in our study were identified as poor metabolizers. Although these four subjects may have had high plasma levels of omeprazole, our study showed significant differences between the effects of famotidine and omeprazole on intragastric acidity. The present results are also supported by an in vitro study. In an autoradiography study, Nakamura et al.19 reported that H2 receptor antagonists were accumulated equally on parietal cells, while proton pump inhibitors were accumulated only on young activated parietal cells. Nakamura et al.19 hypothesized that because other proton pumps are quickly activated, the antisecretory effect of proton pump inhibitors was not faster than that of H2 receptor antagonists in the early phase postadministration. Our study has demonstrated that, under conditions similar to those of fasting patients in ICUs, a single intravenous injection of famotidine resulted in a faster antisecretory effect than that of omeprazole. Stressrelated mucosal bleeding is common in patients admitted to ICUs,20,21 and the mortality rate is high when gastrointestinal bleeding occurs in these patients.22 Prophylactic treatment with intravenous H2 receptor antagonists has been shown to reduce the bleeding rate,23 confirming the importance of raising intragastric pH to prevent or treat stress ulcers. However, the level of intragastric pH necessary for protection against stress-related mucosal damage is not well established, and, therefore, the optimal pH for the prevention of stress ulcers and bleeding is a subject for debate. Maintenance of intragastric pH above 3.5 to 4 is thought to be necessary for preventing stress ulcers,22,24–26 while an intragastric pH of more than 6 is necessary for the treatment of existing stress ulcers.27 Our results show that a single intravenous injection of famotidine has a faster antisecretory effect than that of omeprazole, and these

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results suggest that famotidine is a suitable initial therapy for patients in ICUs. In our study, during the 3-h and 4-h study periods, the pH was greater than 3 for significantly less time after omeprazole treatment than after famotidine treatment, although omeprazole has antisecretory activity and is more effective than H2 receptor antagonists in healing ulcers. This finding may be explained by studies that have shown that the antisecretory activity of omeprazole increases progressively after repeated oral and intravenous administration, with a steady state being achieved after about 5 days.28,29 Another study has shown that a daily dose of omeprazole 40 mg given by intravenous injection was not sufficient to maintain intragastric pH at more than 4 on the first day of treatment.30 However, after 5–7 days’ treatment, oral omeprazole 20 mg was more effective than famotidine 40 mg for normal subjects, patients with duodenal ulcer, and gastroesophageal reflux disease (GERD) patients.31–33 In conclusion, famotidine 20 mg increases intragastric pH more rapidly than omeprazole 20 mg in Helicobacter pylori-negative subjects. This study shows that famotidine 20 mg is more suitable for initial therapy than omeprazole 20 mg, when given as a single intravenous dose. Acknowledgments. This study was supported by a grant from Yamanouchi Pharmaceutical Co., Ltd., Tokyo, Japan.

Y. Abe et al.: Initial effects of omeprazole and famotidine

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